Aggressive brain cancer: Why does immunotherapy fail?

Cancer
New research that now appears in the journal Nature Medicine examined glioblastoma tumors, and the results move scientists closer to understanding why this form of brain cancer does not respond as well to immunotherapy as other cancers.
physicians looking at brain scans
Doctors may soon be able to predict which people with glioblastoma will respond to immunotherapy.

Immunotherapy is a treatment type that aims to boost the immune system in the fight against cancer.

The therapy has proven to be very successful against various aggressive cancers, such as triple-negative breast cancer.

However, immunotherapy actually helps fewer than 1 in 10 people with glioblastoma.

This is a form of brain cancer with a median outlook of only 15–18 months.

So, why does immunotherapy not work as effectively in these tumors? A team of scientists led by Raul Rabadan, Ph.D. — a professor of systems biology and biomedical informatics at Columbia University Vagelos College of Physicians and Surgeons in New York City, NY — set out to investigate.

The role of the PD-1 protein in cancer

As the scientists explain, cancer sometimes blocks the activity of the immune system by affecting a protein called PD-1.

PD-1 is present on immune cells called T cells. There, it helps ensure that the immune system does not overdo its response when it reacts to threats. When PD-1 binds to another protein called PD-L1, it stops T cells from attacking other cells — including tumor cells.

So, some immunotherapy drugs work by blocking PD-1, which “releases the brakes on the immune system” and lets T cells run loose and kill cancer cells.

PD-1 inhibitors are successful in most types of cancer, so Prof. Rabadan and colleagues wondered what effect these drugs would have in glioblastoma. They studied the tumor microenvironment — that is, the cells that maintain the growth of the tumor — in 66 people with glioblastoma.

The researchers examined the tumor microenvironment both before and after treating the tumors with the PD-1 inhibitors nivolumab or pembrolizumab.

Of the 66 glioblastoma cases, 17 responded to immunotherapy for a period of at least 6 months.

Predicting a person’s response to treatment

The researchers’ genomic and transcriptomic analyses demonstrated that the rest of those tumors had significantly more mutations in a gene called PTEN, which normally encodes an enzyme that acts as a tumor suppressor.

Also, Prof. Rabadan and his colleagues found that the higher number of PTEN mutations increased the number of macrophages. These are immune cells that normally “eat” bacteria, viruses, and other microorganisms.

Macrophages also flush out dead cells and cellular waste, as well as stimulating the activity of other immune cells.

In glioblastoma, macrophages triggered growth factors, which fuelled the growth and spread of cancer cells. Also, the analysis revealed that cancer cells in glioblastoma tumors were very tightly packed together, which could make it more difficult for immune cells to penetrate and destroy the tumor.

On the other hand, tumors that responded to treatment had more genetic alterations in the MAPK signaling pathway, which is key for regulating cellular function.

Study co-author Dr. Fabio M. Iwamoto — a neuro-oncologist and assistant professor of neurology at Columbia University Vagelos College of Physicians and Surgeons — comments on the findings, saying:

“These mutations occurred before patients were treated with PD-1 inhibitors, so testing for the mutations may offer a reliable way to predict which patients are likely to respond to immunotherapy.”

The study authors also suggest that glioblastoma tumors that have MAPK mutations may respond better to a combined treatment of PD-1 inhibitors and MAPK-targeted drugs. However, such a therapeutic approach still needs further testing.

Prof. Rabadan states, “We’re still at the very beginning of understanding cancer immunotherapy, particularly in glioblastoma.”

“But our study shows that we may be able to predict which glioblastoma patients might benefit from this therapy. We’ve also identified new targets for treatment that could improve immunotherapy for all glioblastoma patients.”

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